This proposal is for the continuation of a research project in its 4th year of funding, with goals for the characterization of TR2 and TR3 orphan receptors (TR2 and TR3) in prostate cancer. TR2 and TR3 are members of the steroid receptor superfamily that were identified in the P.I.'s laboratory. Based on the past several years' research efforts from the labs of the P.I. and others, we now know TR2 and TR3 may represent master regulators in the prostate and other organs. Target genes and their hormone response elements (from DR1 to DR6) have been isolated and characterized. Data from the P.I.'s lab suggested that TR2 could modulate several important signaling pathways that may play vital roles in the prostate growth, such as (1) Retinoids- RAR/RXR-mediated apoptosis, (2) Vitamin D-VDR-mediated differentiation, and (3) irradiation-p53 -mediated apoptosis. The expression of some viruses (such as SV40 and HPV) can be regulated by TR2. The CNTF signaling pathway can also be regulated by TR2/TR3 expression. Expression of TR3 may be linked to the prostate cancer apoptosis (as demonstrated in LNCaP and PC-3 cells). Based on the above progress, we will propose the following 3 Aims to continue the characterization of TR2 and TR3 in prostate cancer cells: Aim 1, Isolation of trans-acting factors (TAFs) that control expression of TR2 and TR3; Aim 2, Isolation of cofactors (coactivators/corepressors) that can modulate the TR2/TR3 functions; and Aim 3, To study if induction of TR3 may link to the apoptosis in human prostate tumor. The success of this proposal will not only allow us to better understand the molecular mechanism of TR2/TR3, it may also help us to find new signaling pathways in the prostate that may contribute to the development of new drugs/therapies for the battle against prostate cancer.